The consequences of the effects of the chemotherapeutic drug (vincristine) in organs and the influence on the bioavailability of two radio-biocomplexes used for bone evaluations in balb/c female mice

The development of animal model to evaluate the toxicological action of compounds used as pharmaceutical drugs is desired. The model described in this work is based on the capability of drugs to alter the bioavailability of radiopharmaceuticals (radiobiocomplexes) labeled with technetium-99 m(99mTc). There are evidences that the bioavailability or the pharmacokinetic of radiobiocomplexes can be modified by some factors, as drugs, due to their toxicological action in specific organs. Vincristine is anatural product that has been utilized in oncology. The vincristine effect on the bioavailability of the radiobiocomplexes 99mTc- ethylenediphosphonic acid (99mTc-MDP) and 99mTc-pyrophosphate (99mTc- PYP) in Balb/c female mice was evaluated. The fragments of kidney were processed to light microscopy and transmission electron microscopy. The aim of this work was to study at structural and ultrastructural levels the alterations caused by vincristine in organs. One hour after the last dose ofvincristine, 99mTc-PYP or 99mTc-MDP was injected, the animals were sacrificed and the percentage of radioactivity (%ATI) was determined in the isolated organs. Concerning 99mTc-PYP, the %ATI (i) decreased in spleen, thymus, lymph nodes (inguinal and mesentheric), kidney, lung, liver, pancreas, stomach, heart and brain and (ii) increased in bone and thyroid. Concerning 99mTc-MDP, the %ATI (iii) decreased in spleen, thymus, lymph nodes (inguinal and mesentheric), kidney, liver, pancreas,stomach, heart, brain, bone, ovary and uterus. In conclusion, the toxic effect of vincristine in determined organs could be responsible for the alteration of the uptake of the studied radiobiocomplexes

Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis

Background Ultrasound (US) has largely replaced contrast venography as the definitive diagnostic test for deep vein thrombosis (DVT). We aimed to derive a definitive estimate of the diagnostic accuracy of US for clinically suspected DVT and identify study-level factors that might predict accuracy. Methods We undertook a systematic review, meta-analysis and meta-regression of diagnostic cohort studies that compared US to contrast venography in patients with suspected DVT. We searched Medline, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, the ACP Journal Club, and citation lists (1966 to April 2004). Random effects meta-analysis was used to derive pooled estimates of sensitivity and specificity. Random effects meta-regression was used to identify study-level covariates that predicted diagnostic performance. Results We identified 100 cohorts comparing US to venography in patients with suspected DVT. Overall sensitivity for proximal DVT (95% confidence interval) was 94.2% (93.2 to 95.0), for distal DVT was 63.5% (59.8 to 67.0), and specificity was 93.8% (93.1 to 94.4). Duplex US had pooled sensitivity of 96.5% (95.1 to 97.6) for proximal DVT, 71.2% (64.6 to 77.2) for distal DVT and specificity of 94.0% (92.8 to 95.1). Triplex US had pooled sensitivity of 96.4% (94.4 to 97.1%) for proximal DVT, 75.2% (67.7 to 81.6) for distal DVT and specificity of 94.3% (92.5 to 95.8). Compression US alone had pooled sensitivity of 93.8 % (92.0 to 95.3%) for proximal DVT, 56.8% (49.0 to 66.4) for distal DVT and specificity of 97.8% (97.0 to 98.4). Sensitivity was higher in more recently published studies and in cohorts with higher prevalence of DVT and more proximal DVT, and was lower in cohorts that reported interpretation by a radiologist. Specificity was higher in cohorts that excluded patients with previous DVT. No studies were identified that compared repeat US to venography in all patients. Repeat US appears to have a positive yield of 1.3%, with 89% of these being confirmed by venography. Conclusion Combined colour-doppler US techniques have optimal sensitivity, while compression US has optimal specificity for DVT. However, all estimates are subject to substantial unexplained heterogeneity. The role of repeat scanning is very uncertain and based upon limited data

MMP-9 gene variants increase the risk for non-atopic asthma in children

<p>Abstract</p> <p>Background</p> <p>Atopic and non-atopic wheezing may be caused by different etiologies: while eosinophils are more important in atopic asthmatic wheezers, neutrophils are predominantly found in BAL samples of young children with wheezing. Both neutrophils as well as eosinophils may secrete matrix metalloproteinase 9 (MMP-9). Considering that MMP-9 plays an important role in airway wall thickening and airway inflammation, it may influence the development of obstructive airway phenotypes in children. In the present study we investigated whether genetic variations in <it>MMP-9 </it>influence the development of different forms of childhood asthma.</p> <p>Methods</p> <p>Genotyping of four HapMap derived tagging SNPs in the <it>MMP-9 </it>gene was performed using MALDI-TOF MS in three cross sectional study populations of German children (age 9-11; N = 4,264) phenotyped for asthma and atopic diseases according to ISAAC standard procedures. Effects of single SNPs and haplotypes were studied using SAS 9.1.3 and Haploview.</p> <p>Results</p> <p>SNP rs2664538 significantly increased the risk for non-atopic wheezing (OR 2.12, 95%CI 1.40-3.21, p < 0.001) and non-atopic asthma (OR 1.66, 95%CI 1.12-2.46, p = 0.011). Furthermore, the minor allele of rs3918241 may be associated with decreased expiratory flow measurements in non-atopic children. No significant effects on the development of atopy or total serum IgE levels were observed.</p> <p>Conclusions</p> <p>Our results have shown that homozygocity for <it>MMP-9 </it>variants increase the risk to develop non-atopic forms of asthma and wheezing, which may be explained by a functional role of MMP-9 in airway remodeling. These results suggest that different wheezing disorders in childhood are affected differently by genetic alterations.</p

Interleukin-17A mRNA and protein expression within cells from the human bronchoalveolar space after exposure to organic dust

BACKGROUND: In mice, the cytokine interleukin (IL)-17A causes a local accumulation of neutrophils within the bronchoalveolar space. IL-17A may thereby also contribute to an increased local proteolytic burden. In the current study, we determined whether mRNA for IL-17A is elevated and protein expression of IL-17A occurs locally in inflammatory cells within the human bronchoalveolar space during severe inflammation caused by organic dust. We also assessed the expression of the elastinolytic protease MMP-9 in this airway compartment. METHODS: Six healthy, non-smoking human volunteers were exposed to organic dust in a swine confinement, a potent stimulus of neutrophil accumulation within the human bronchoalveolar space. Bronchoalveolar lavage (BAL) fluid was harvested 2 weeks before and 24 hours after the exposure and total and differential counts were conducted for inflammatory BAL cells. Messenger RNA for IL-17A was measured using reverse transcript polymerase chain reaction-enzyme linked immunoassay (RT-PCR-ELISA). Intracellular immunoreactivity (IR) for IL-17A and MMP-9, respectively, was determined in BAL cells. RESULTS: The exposure to organic dust caused more than a forty-fold increase of mRNA for IL-17A in BAL cells. IL-17A immunoreactivity was detected mainly in BAL lymphocytes, and the number of these IL-17A expressing lymphocytes displayed an eight-fold increase, even though not statistically significant. The increase in IL-17A mRNA was associated with a substantial increase of the number of BAL neutrophils expressing MMP-9 immunoreactivity. CONCLUSION: Exposure to organic dust increases local IL-17A mRNA and because there is intracellular expression in BAL lymphocytes, this suggests that IL-17A protein can originate from lymphocytes within the human bronchoalveolar space. The fact that the increased IL-17A mRNA is associated with an increased number of MMP-9-expressing neutrophils is compatible with IL-17A increasing the local proteolytic burden through its neutrophil-accumulating effect

A randomized, double-blind, placebo-controlled trial to assess the efficacy of topiramate in the treatment of post-traumatic stress disorder

<p>Abstract</p> <p>Background</p> <p>Topiramate might be effective in the treatment of posttraumatic stress disorder (PTSD) because of its antikindling effect and its action in both inhibitory and excitatory neurotransmitters. Open-label studies and few controlled trials have suggested that this anticonvulsant may have therapeutic potential in PTSD. This 12-week randomized, double-blind, placebo-controlled clinical trial will compare the efficacy of topiramate with placebo and study the tolerability of topiramate in the treatment of PTSD.</p> <p>Methods and design</p> <p>Seventy-two adult outpatients with DSM-IV-diagnosed PTSD will be recruited from the violence program of Federal University of São Paulo Hospital (UNIFESP). After informed consent, screening, and a one week period of wash out, subjects will be randomized to either placebo or topiramate for 12 weeks. The primary efficacy endpoint will be the change in the Clinician-administered PTSD scale (CAPS) total score from baseline to the final visit at 12 weeks.</p> <p>Discussion</p> <p>The development of treatments for PTSD is challenging due to the complexity of the symptoms and psychiatric comorbidities. The selective serotonin reuptake inhibitors (SSRIs) are the mainstream treatment for PTSD, but many patients do not have a satisfactory response to antidepressants. Although there are limited clinical studies available to assess the efficacy of topiramate for PTSD, the findings of prior trials suggest this anticonvulsant may be promising in the management of these patients.</p> <p>Trial Registration</p> <p>NCT 00725920</p